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1.  Combined nevi of the conjunctiva. 
PURPOSE: To report the clinical and histologic features of combined nevi of the conjunctiva, a type of nevus that is not uncommon in the skin but has rarely been reported in the conjunctiva. METHODS: Conjunctival nevi and melanomas from the files of the University of California, San Francisco, eye pathology laboratory were reviewed from 1984 to 1999 for the presence of features of both standard nevocytic nevi and blue nevi. Clinical histories and, when available, clinical photographs were obtained. RESULTS: Thirty-one combined nevi were discovered during the 15-year period between 1984 and 1999. One case before 1984 had been incorrectly diagnosed as a junctional nevus. The dendritic and spindle-shaped blue nevus cells had been overlooked because they were not recognized as distinct from the standard nevocytic nevus cells. The recognition of a blue as well as a brown color, a deep as well as a superficial component in the lesion, or a history of pigmentation since birth may help to establish the correct clinical diagnosis and prevent an unnecessarily deep surgical resection. Although growth of the lesion or "satellites" in some patients may favor a clinical diagnosis of melanoma, none of the lesions in this series were malignant. CONCLUSION: Despite a paucity of reports of combined nevi of the conjunctiva in the medical literature, this type of nevus--a combination of a nevocytic and a blue nevus--is common and has been overlooked in the past.
Images
PMCID: PMC1298259  PMID: 10703123
2.  Imaging Microscopic Pigment Chemistry in Conjunctival Melanocytic Lesions Using Pump-Probe Laser Microscopy 
Purpose.
To report the application of a novel imaging technique, pump-probe microscopy, to analyze patterns of pigment chemistry of conjunctival melanocytic lesion biopsies.
Methods.
Histopathologic specimens of eight previously excised conjunctival melanocytic lesions were analyzed with pump-probe microscopy. The technique uses a laser scanning microscope with a two-color pulsed laser source to distinguish hemoglobin, eumelanin, and pheomelanin pigment based on differences in transient excited state and ground state photodynamics. The pump-probe signatures of conjunctival melanins were compared with cutaneous melanins. The distributions of hemoglobin, eumelanin, and pheomelanin were analyzed, and pump-probe images were correlated with adjacent hematoxylin and eosin (H&E)-stained sections.
Results.
The pump-probe signatures of conjunctival melanins are similar, but not identical to cutaneous melanins. In addition, there are qualitative and quantitative differences in the structure and pigment chemistry of conjunctival benign nevi, primary acquired melanosis of the conjunctiva (PAM), and conjunctival melanomas. The pump-probe images correlated well with histopathologic features observed in the adjacent H&E-stained sections, and provided a label-free means of discerning conjunctival anatomic features and pathologic benign or malignant tissue.
Conclusions.
Pump-probe laser microscopy shows promise as an adjuvant diagnostic tool in evaluation of ocular melanocytic lesions based on morphologic correlation with the histopathology results and pigment chemistry. This initial study suggests systematic differences in pigmentation patterns among conjunctival benign nevi, primary acquired melanosis, and melanomas. In addition, pump-probe microscopy has the potential for use as a noninvasive “in vivo” optical biopsy technique to aid clinical and surgical management of conjunctival melanocytic lesions.
Using pump-probe microscopy, a multiphoton technique that images absorptive pigments, we analyzed the microscopic distribution of melanins in biopsy sections of conjunctival melanocytic lesions, and found differences among conjunctival benign nevi, primary acquired melanosis, and melanomas.
doi:10.1167/iovs.13-12432
PMCID: PMC3805089  PMID: 24065811
conjunctival melanoma; primary acquired melanosis; benign conjunctival nevus; pump-probe microscopy; multiphoton microscopy
3.  The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions 
C-Kit (CD117), the receptor for the stem cell factor, a growth factor for melanocyte migration and proliferation, has shown differential immunostaining in various benign and malignant melanocytic lesions. The purpose of this study is to compare c-Kit immunostaining in benign nevi and in primary and metastatic malignant melanomas, to determine whether c-Kit can aid in the differential diagnosis of these lesions. c-Kit immunostaining was performed in 60 cases of pigmented lesions, including 39 benign nevi (5 blue nevi, 5 intra-dermal nevi, 3 junctional nevi, 15 cases of primary compound nevus, 11 cases of Spitz nevus), 18 cases of primary malignant melanoma and 3 cases of metastatic melanoma. The vast majority of nevi and melanomas examined in this study were positive for c-Kit, with minimal differences between benign and malignant lesions. C-Kit cytoplasmatic immunoreactivity in the intraepidermal proliferating nevus cells, was detected in benign pigmented lesions as well as in malignant melanoma, increasing with the age of patients (P=0.007) in both groups. The patient’s age at presentation appeared to be the variable able to cluster benign and malignant pigmented lesions. The percentage of c-Kit positive intraepidermal nevus cells was better associated with age despite other variables (P=0.014). The intensity and percentage of c-Kit positivity in the proliferating nevus cells in the dermis was significantly increased in malignant melanocytic lesions (P=0.015 and P=0.008) compared to benign lesions (compound melanocytic nevi, Spitz nevi, intradermal nevi, blue nevi). Immunostaning for c-Kit in metastatic melanomas was negative. Interestingly in two cases of melanoma occurring on a pre-existent nevus, the melanoma tumor cells showed strong cytoplasmatic and membranous positivity for c-kit, in contrast with the absence of any immunoreactivity in pre-existent intradermal nevus cells. C-Kit does not appear to be a strong immunohistochemical marker for distinguishing melanoma from melanocytic nevi, if we consider c-Kit expression in intraepidermal proliferating cells. The c-Kit expression in proliferating melanocytes in the dermis could help in the differential diagnosis between a superficial spreading melanoma (with dermis invasion) and a compound nevus or an intradermal nevus. Finally, c-Kit could be a good diagnostic tool for distinguishing benign compound nevi from malignant melanocytic lesions with dermis invasion and to differentiate metastatic melanoma from primary melanoma.
doi:10.4081/ejh.2011.e20
PMCID: PMC3284155  PMID: 22193299
c-kit; melanoma; nevi.
4.  Association between Cutaneous Nevi and Breast Cancer in the Nurses' Health Study: A Prospective Cohort Study 
PLoS Medicine  2014;11(6):e1001659.
Using data from the Nurses' Health Study, Jiali Han and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk.
Methods and Findings
We followed 74,523 female nurses for 24 y (1986–2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98–1.10 for 1–5 nevi; 1.15, 95% CI, 1.00–1.31 for 6–14 nevi, and 1.35, 95% CI, 1.04–1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%–9.33%) for women with 1–5 nevi, 9.75% (95% CI, 8.48%–11.11%) for women with 6–14 nevi, and 11.4% (95% CI, 8.82%–14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)–positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02–1.16 for ER+/progesterone receptor [PR]–positive tumors; 1.08, 95% CI, 0.94–1.24 for ER+/PR− tumors; and 0.99, 95% CI, 0.86–1.15 for ER−/PR− tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched controls with plasma hormone measurements, the multivariable-adjusted odds ratio for every five nevi attenuated from 1.25 (95% CI, 0.89–1.74) to 1.16 (95% CI, 0.83–1.64) after adjusting for plasma hormone levels. Key limitations in this study are that cutaneous nevi were self-counted in our cohort and that the study was conducted in white individuals, and thus the findings do not necessarily apply to other populations.
Conclusions
Our results suggest that the number of cutaneous nevi may reflect plasma hormone levels and predict breast cancer risk independently of previously known factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
One woman in eight will develop breast cancer during her lifetime. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably (which leads to the formation of a lump in the breast) and to move around the body (metastasize). The treatment of breast cancer, which is diagnosed using mammography (a breast X-ray) or manual breast examination and biopsy, usually involves surgery to remove the lump, or the whole breast (mastectomy) if the cancer has started to metastasize. After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells and may also be given drugs that block the action of estrogen and progesterone, female sex hormones that stimulate the growth of some breast cancer cells. Globally, half a million women die from breast cancer each year. However, in developed countries, nearly 90% of women affected by breast cancer are still alive five years after diagnosis.
Why Was This Study Done?
Several sex hormone–related factors affect breast cancer risk, including at what age a woman has her first child (pregnancy alters sex hormone levels) and her age at menopause, when estrogen levels normally drop. Moreover, postmenopausal women with high circulating levels of estrogen and testosterone (a male sex hormone) have an increased breast cancer risk. Interestingly, moles (nevi)—dark skin blemishes that are a risk factor for the development of melanoma, a type of skin cancer—often darken or enlarge during pregnancy. Might the number of nevi be a marker of hormone levels, and could nevi counts therefore be used to predict an individual's risk of breast cancer? In this prospective cohort study, the researchers look for an association between number of nevi and breast cancer risk among participants in the US Nurses' Health Study (NHS). A prospective cohort study enrolls a group of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of certain diseases. The NHS, which enrolled 121,700 female nurses aged 30–55 years in 1976, is studying risk factors for cancer and other chronic diseases in women.
What Did the Researchers Do and Find?
In 1986, nearly 75,000 NHS participants (all of whom were white) reported how many nevi they had on their left arm. Over the next 24 years, 5,483 invasive breast cancers were diagnosed in these women. Compared to women with no nevi, women with increasing numbers of nevi had a higher risk of breast cancer after adjustment for known breast cancer risk factors. Specifically, among women with 1–5 nevi, the hazard ratio (HR) for breast cancer was 1.04, whereas among women with 15 or more nevi the HR was 1.35. An HR compares how often a particular event occurs in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event. Over 24 years of follow-up, the absolute risk of developing breast cancer was 8.48% in women with no nevi but 11.4% for women with 15 or more nevi. Notably, postmenopausal women with six or more nevi had higher blood levels of estrogen and testosterone than women with no nevi. Finally, in a subgroup analysis, the association between number of nevi and breast cancer risk disappeared after adjustment for hormone levels.
What Do These Findings Mean?
These findings support the hypothesis that the number of nevi reflects sex hormone levels in women and may predict breast cancer risk. Notably, they show that the association between breast cancer risk and nevus number was independent of known risk factors for breast cancer, and that the risk of breast cancer increased with the number of nevi in a dose-dependent manner. These findings also suggest that a hormonal mechanism underlies the association between nevus number and breast cancer risk. Because this study involved only white participants, these findings may not apply to non-white women. Moreover, the use of self-reported data on nevus numbers may affect the accuracy of these findings. Finally, because this study is observational, these findings are insufficient to support any changes in clinical recommendations for breast cancer screening or diagnosis. Nevertheless, these data and those in an independent PLOS Medicine Research Article by Kvaskoff et al. support the need for further investigation of the association between nevi and breast cancer risk and of the mechanisms underlying this relationship.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001659.
An independent PLOS Medicine Research Article by Kvaskoff et al. also investigates the relationship between nevi and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the Nurses' Health Study is available
doi:10.1371/journal.pmed.1001659
PMCID: PMC4051600  PMID: 24915186
5.  Comparative genomic hybridization for the diagnosis of melanoma 
Despite advancements in protocols, a subset of melanocytic lesions continues to pose diagnostic challenges. This is particularly true in the pediatric population where certain congenital nevi mimic melanoma. Recently, comparative genomic hybridization (CGH) has been utilized to support diagnoses of melanocytic lesions based on DNA copy number changes. Because distinct differences in copy number changes have been shown to occur in malignant melanoma and benign nevi, CGH can be a useful adjunct when diagnosis based on histology alone is indeterminate. The authors discuss the benefits of using CGH to aid in the diagnosis of melanocytic lesions that are difficult to characterize as malignant or benign based on clinical and histologic features alone. This paper presents a brief clinical report and review of the literature. A 13-year-old Caucasian male presented to an academic tertiary care medical center after a shave biopsy unexpectedly revealed malignant melanoma with positive deep margins. Following complete excisional biopsy, the diagnosis of malignant melanoma with depth of 0.92 mm was confirmed, both by the home institution's pathologist and by consultant dermatopathologists at two separate academic tertiary medical centers. Sentinel lymph node biopsy revealed a small focus of metastatic melanoma, this lead to a left-sided modified radical neck dissection. All nodes removed were negative for disease, and surgical and postsurgical care was uncomplicated. Before proceeding with interferon therapy, CGH was performed on the tissue from the primary lesion. Other than a slight amplification of chromosome 16p, no other aberrations were detected favoring a benign lesion. Ultimately, the diagnosis was amended to compound melanocytic nevus of the nose with benign nevus cell rest in the sentinel node. While histopathologic evaluation is the current gold standard for the diagnosis of melanoma, there are many cases where it is inaccurate. The use of CGH in the evaluation of histologically equivocal lesions may allow certain patients to avoid invasive procedures and associated morbidities. The authors propose that, in these select diagnostically challenging cases, tissue analyses by CGH may be beneficial before proceeding to more invasive procedures such as sentinel node biopsy and complete lymphadenectomy.
doi:10.1007/s00238-009-0369-9
PMCID: PMC2837230  PMID: 20234825
Melanoma; Diagnosis; Nevus; Nevi; Comparative genomic hybridization
6.  Correlation of clinical pigmentary characteristics with histopathologically-confirmed dysplastic nevi in nonfamilial melanoma patients. Studies of melanocytic nevi IX. 
British Journal of Cancer  1991;64(5):943-947.
The dysplastic melanocytic nevus (DMN) is the key clinical marker for the familial dysplastic nevus syndrome and has also been associated with high risk for non-familial melanoma. Characterisations of DMN itself have been qualitative and on a case-by-case basis. In this study, we provided clinical and histological characterisations for each of 150 pigmented lesions from 150 patients with prior malignant melanoma. The steps involved in the study were as follows: (1) The two to four clinicians characterised pigmented lesions on each of 150 patients, and the lesion closest in characteristics to an atypical nevus was quantitatively described based on size, border characteristics and colour characteristics; (2) The lesion was then removed and independently quantified by a single dermatopathologist without knowledge of the clinical features; (3) We computed the correlation between each of the clinical variables and each of the histologic features for each of the 150 patients. Histologic diagnosis of dysplastic nevus was strongly associated with total number of palpable arm nevi, total number of any arm nevi, total number of nevi on the body of any type, and total number of clinically atypical nevi on the body (correlation coefficients 23.2% to 30.4% with P less than 0.01 in each instance). There were also strong correlations between the counts of numbers of nevi and certain types of architectural histologic features, including fusion (bridging of junctional nests), lymphocyte response and fibroplasia of the papillary dermis. Histologic evaluation of solar elastosis was negatively correlated with total numbers of nevi and total number of clinically atypical nevi (P less than 0.01). Freckling on forearm and on shoulders showed no significant positive or negative correlations with any of the histologic features nor with overall diagnosis of dysplastic nevus. We conclude that observations regarding total numbers of nevi (either normal or clinically atypical nevi) are correlated with nuclear and architectural histologic dysplasia on biopsy of the most atypical pigmented lesions.
PMCID: PMC1977446  PMID: 1931621
7.  The ultrastructure of conjunctival melanocytic tumors. 
The ultrastructure of conjunctival melanocytic lesions in 49 patients was evaluated to find significant differences between benign and malignant cells. The patients studied included 9 with benign epithelial (racial) melanosis, 2 with pigmented squamous cell papillomas, 16 with conjunctival nevi, 18 with primary acquired melanosis, and 11 with invasive nodules of malignant melanoma. In benign epithelial melanosis, dendritic melanocytes were situated along the basement membrane region of the conjunctival epithelium, with one basilar dendritic melanocyte lodged among every five or six basilar keratinocytes. The dendritic melanocytes extended arborizing cellular processes between the basilar and among the suprabasilar keratinocytes, which manifested considerable uptake of melanin granules into their cytoplasm. The benign dendritic melanocytes possessed nuclei with clumped heterochromatin at the nuclear membrane, small, tightly wound nucleoli, and large, elongated, fully melaninized melanin granules. In two patients with benign hyperplasia of the dendritic melanocytes, occasional dendritic melanocytes were located in a suprabasilar position, but were always separated from each other by keratinocytes or their processes. In the two black patients with benign pigmented squamous papillomas, the benign dendritic melanocytes were located hapharzardly at all levels of the acanthotic epithelium and not just along the basement membrane region. Melanin uptake by the proliferating keratinocytes was minimal. In benign melanocytic nevi of the conjunctiva, nevus cells within the intraepithelial junctional nests displayed a more rounded cellular configuration; short villi and broader cellular processes suggestive of abortive dendrites were found. The nuclear chromatin pattern was clumped at the nuclear membrane, but the nucleoli were somewhat larger than those of benign dendritic melanocytes in epithelial melanosis. The melanosomes were smaller and rounder than those in dendritic melanocytes and exhibited more haphazard arrangements of the melanofilaments, which were only partially melaninized. Mitochondria were more numerous than in dendritic melanocytes, and monoribosomes predominated over polyribosomes. Cytoplasmic filaments were inconspicuous. Cells in the immediate subepithelial connective tissue zone had features identical to those of the cells within the junctional nests. Smaller, lymphocytoid cells with less numerous and more rudimentary melanosomes were found in the middle and deeper portions of the lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
Images
PMCID: PMC1298677  PMID: 6398936
8.  Low rates of clinical recurrence following biopsy of benign to moderately atypical dysplastic melanocytic nevi 
Background
Little is known about the recurrence/persistence rates of dysplastic nevi (DN) following biopsy, and whether incompletely removed DN should be re-excised to prevent recurrence.
Objective
Our purpose was to determine the recurrence rates of previously biopsied DN, and to assess whether biopsy method, margin involvement, congenital features, epidermal location, and degree of dysplasia are associated with recurrence.
Methods
Patients having a history of nevus biopsy at least two years prior were assessed for clinical recurrence. Slides of original lesions were re-reviewed by a dermatopathologist.
Results
A total of 271 nevus biopsy sites were assessed in 115 patients. Of 195 DN with greater than two years of follow-up, seven (3.6%) demonstrated recurrence on clinical exam. Ninety-eight DN had a follow-up period of at least four years with no clinical recurrence. Of 61 benign nevus biopsy sites examined, clinical recurrence was observed in two (3.3%). For all nevi, recurrence was significantly associated with shave biopsy technique but not with nevus dysplasia or subtype, or the presence of positive margin or congenital features.
Limitations
Most biopsies were performed in a pigmented lesion clinic at a single tertiary referral center. Determinations of nevus recurrence were made on clinical rather than histologic grounds, and follow-up times were limited in some cases.
Conclusion
In this cohort, rates of clinical recurrence following biopsy of dysplastic and benign nevi were extremely low. Re-excision of nevi, including moderately dysplastic nevi with a positive margin, may not be necessary.
doi:10.1016/j.jaad.2009.06.080
PMCID: PMC2886801  PMID: 20018406
nevi; recurrence; biopsy; dysplastic
9.  Association between Melanocytic Nevi and Risk of Breast Diseases: The French E3N Prospective Cohort 
PLoS Medicine  2014;11(6):e1001660.
Using data from the French E3N prospective cohort, Marina Kvaskoff and colleagues examine the association between number of cutaneous nevi and the risk for breast cancer.
Please see later in the article for the Editors' Summary
Background
While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk.
Methods and Findings
We prospectively analyzed data from E3N, a cohort of French women aged 40–65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990–15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with “very many” nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01–1.27 versus “none”; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674–4,649) per 100,000 women with “very many” nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose–response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD.
Conclusions
Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2012, nearly 1.7 million women worldwide discovered they had breast cancer, and about half a million women died from the disease. Breast cancer begins when cells in the breast acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). Uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump, or, if the cancer has started to spread, by removal of the whole breast (mastectomy). Surgery is usually followed by radiotherapy or chemotherapy to kill any remaining cancer cells. Because the female sex hormones estrogen and progesterone stimulate the growth of some tumors, drugs that block hormone receptors are also used to treat receptor-positive breast cancer. Nowadays, the prognosis (outlook) for women with breast cancer is good, and in developed countries, nearly 90% of affected women are still alive five years after diagnosis.
Why Was This Study Done?
Several hormone-related factors affect a woman's chances of developing breast cancer. For example, women who have no children or who have them late in life have a higher breast cancer risk than women who have several children when they are young because pregnancy alters sex hormone levels. Interestingly, the development of moles (nevi)—dark skin blemishes that are risk factors for the development of melanoma, a type of skin cancer—may also be affected by estrogen and progesterone. Thus, the number of nevi might be a marker of blood hormone levels and might predict breast cancer risk. In this prospective cohort study, the researchers test this hypothesis by investigating the association between how many moles a woman has and her breast cancer risk. A prospective cohort study enrolls a group (cohort) of people, determines their baseline characteristics, and follows them over time to see which characteristics are associated with the development of specific diseases.
What Did the Researchers Do and Find?
In 1990, the E3N prospective cohort study enrolled nearly 100,000 French women (mainly school teachers) aged 40–65 years to investigate cancer risk factors. The women completed a baseline questionnaire about their lifestyle and medical history, and regular follow-up questionnaires that asked about cancer occurrence. In the initial questionnaire, the women indicated whether they had no, a few, many, or very many moles. Between 1990 and 2008, nearly 6,000 women in the cohort developed breast cancer. Using statistical methods to calculate hazard ratios (an “HR” compares how often a particular event happens in two groups with different characteristics; an HR greater than one indicates that a specific characteristic is associated with an increased risk of the event), the researchers report that women with “very many” nevi had a significantly higher breast cancer risk (a higher risk that was unlikely to have occurred by chance) than women with no nevi. Specifically, the age-adjusted HR for breast cancer among women with “very many” nevi compared to women with no nevi was 1.17. After adjustment for a personal history of benign (noncancerous) breast disease and a family history of breast cancer (two established risk factors for breast cancer), the association between nevi and breast cancer risk among the whole cohort became nonsignificant. Notably, however, the association among only premenopausal women remained significant after full adjustment (HR = 1.34), which corresponded to an increase in ten-year absolute risk of invasive breast cancer from 2,515 per 100,000 women with no nevi to 3,370 per 100,000 women with “very many” nevi.
What Do These Findings Mean?
These findings suggest that among premenopausal women there is a modest association between nevi number and breast cancer risk. This noncausal relationship may indicate that nevi and breast diseases are affected in similar ways by hormones or share common genetic factors, but the accuracy of these findings may be limited by aspects of the study design. For example, self-report of nevi numbers using a qualitative scale may have introduced some inaccuracies into the estimates of the association between nevi number and breast cancer risk. Most importantly, these findings are insufficient to support the use of nevi counts in breast cancer screening or diagnosis. Rather, together with the findings reported by Zhang et al. in an independent PLOS Medicine Research Article, they suggest that further studies into the biological mechanisms underlying the relationship between nevi and breast cancer and the association itself should be undertaken.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001660.
This study is further discussed in a PLOS Medicine Perspective by Fuhrman and Cardenas
An independent PLOS Medicine Research Article by Zhang et al. also investigates the relationship between nevi number and breast cancer risk
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information for patients and professionals about breast cancer; it also has a fact sheet on moles
Cancer Research UK, a not-for profit organization, provides information about cancer, including detailed information on breast cancer
The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
More information about the E3N prospective cohort study is available; detailed information is available in French
doi:10.1371/journal.pmed.1001660
PMCID: PMC4051602  PMID: 24915306
10.  A Clinicopathologic Study of Excised Conjunctival Lesions 
Purpose:
This study was aimed at to determine the frequency of excised conjunctival lesions in a patient population treated over a 10-year period.
Materials and Methods:
The data of all excised conjunctival lesions with tissue diagnoses from 1998 to 2008 in the pathology department were analyzed.
Results:
The patient group comprised 192 conjunctival specimens; 106 (55.2%) obtained from male patients and 86 (44.8 %) from female patients. The age range was 75 years with a mean age of 27.07 ± 17 years. The most frequent excised lesions were pyogenic granulomas, which represented 30.7% (59 cases). Pigmented epithelial tumors were the second most common benign conjunctival lesions (44 cases, 22.9%). Out of these cases, compound nevus represented 86.4% (38 cases) and junctional nevus represented 6.8% (3 cases). Primary acquired melanosis and subepithelial nevus were reported in two cases (4.5%) and one case (2.3%), respectively. Cystic lesions represented 12% (23 cases). These were mostly ductal retention cysts in 16 cases (70%), occupying the fornix in eight cases. Ocular surface squamous neoplasia (OSSN) was detected in 21 cases (10.9%) significantly affecting an older age group as compared to other lesions (mean age 45.9 ± 16.7). Other less frequent lesions included papilloma (10 cases, 2.5%), dermolipoma (8 cases, 4.2%), solid dermoid (3 cases, 1.6%), hemangioma (15 cases, 7.8%), and benign reactive lymphoid hyperplasia (four cases, 2.1%).
Conclusion:
Benign lesions were the most frequent histologically diagnosed conjunctival lesions. The true malignant lesions were lower than what has been described in many reports. The significant proportion of precancerous OSSN can be attributed to sun exposure and ultraviolet light in Egypt.
doi:10.4103/0974-9233.75886
PMCID: PMC3085152  PMID: 21572734
Conjunctiva; Hemangioma; Nevus; Ocular Surface Squamous Neoplasia; Papilloma
11.  A juvenile case of conjunctival atypical nevus 
Diagnostic Pathology  2013;8:64.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2973228795724608
Melanocytic nevi are the most common tumors of the conjunctiva, accounting for 28% of all neoplastic lesions. These tumors, despite their benign behavior, share some atypical histological features with nevi found in other anatomic sites like the genital and acral regions, globally designated as nevi with site-related atypia. Moreover, in children and adolescents, rapidly growing conjunctival nevi show sometimes worrisome histological patterns in association with a prominent inflammatory infiltrate that may lead to diagnostic problems. In this paper we describe a juvenile compound nevus characterized by marked melanocytic atypia and severe inflammation, which can be considered a rare case of juvenile conjunctival atypical nevus. The final diagnosis relied on morphological and immunohistochemical characterization of the large epithelioid melanocytic cells, and on the results of FISH analysis.
doi:10.1186/1746-1596-8-64
PMCID: PMC3662158  PMID: 23607499
12.  Ocular adnexal lymphoproliferative disorders in an ophthalmic referral center in Saudi Arabia 
Saudi Journal of Ophthalmology  2013;27(3):227-230.
Purpose
To study the pattern of ocular adnexal lymphoproliferative disorders (OALD) in an ophthalmic referral center in Saudi Arabia and to review their, histopathological characteristics with clinical correlation.
Methods
Retrospective chart review of 40 cases of patients who underwent incisional biopsy with the suspected diagnosis of periocular and/or adnexal lymphoid lesions over the period: 2000–2012 at the King Khaled Eye Specialist Hospital (KKESH), Riyadh, Saudi Arabia. The routine histopathologic slides are reviewed by a single pathologist to identify cases of Benign Reactive Lymphoid Hyperplasia (RLH), Atypical Lymphoid Hyperplasia and probable lymphoma. The identification of the specific types of lymphoma is performed at a tertiary general hospital: King Faisal Specialist Hospital and Research Centre (KFSH&RC).
Results
Forty patients are included with an age range of 11–91 years and a median of 36 years. The males constitute 70% and females 30% of the cases. The right eye and/or orbit are involved in 48%. The left eye is involved in 45% while a bilateral disease is found in 7.5%. The median duration of symptoms is 5 months. The site distribution is conjunctiva (42.5%), orbit (25%), lacrimal gland (12.5%), eyelid (10%), lacrimal sac (7.5%) and caruncle (2.5%). One case is excluded after histopathologic diagnosis of malignant melanoma. Diagnosis in the remaining 39 cases includes: RLH in 14 cases (35%), atypical lymphoid hyperplasia in three cases (9%), and lymphoma in 22 cases (56%). Classification of the lymphoma group is: extranodal marginal zone lymphoma (EMZL) in 9/22 cases (41%), diffuse large B cell lymphoma (DLBCL) in 4/22 cases (18%), Castelman’s disease in 3/22 cases (14%), Burkitt’s lymphoma in 2/22 cases (9%), follicular lymphoma and T cell-rich B cell lymphoma: one case each (4.5%).Two cases remain unclassified.
Conclusion
We have a wide age range which is comparable to other studies. Our results show male predominance and the commonest site of involvement is conjunctival, however if RLH cases are excluded, the commonest site for lymphoma is orbit/lacrimal gland in 45% followed by conjunctival in 23%. The commonest type of lymphoma is: EMZL in 41% followed by DLBCL in 18% then other types of lymphoma including follicular lymphoma.
doi:10.1016/j.sjopt.2013.07.003
PMCID: PMC3770215  PMID: 24227991
Lymphoma; Orbit; Adnexal; Lymphoid hyperplasia; Lacrimal
13.  Unilateral Nevus of Ota with Bilateral Nevus of Ito and Palatal Lesion: A Case Report with a Proposed Clinical Modification of Tanino's Classification 
Indian Journal of Dermatology  2013;58(4):286-289.
Nevus of Ota and nevus of Ito are rare dermal melanocytoses. Nevus of Ota may be very rarely associated with the nevus of Ito and other extra cutaneous features. Both nevi are similar in all respect apart from the area of distribution. Bilateral distribution of nevus of Ito is seldom reported in the literature. A 24-year-old male patient reported with nevus of Ota of the right side of his face since his infancy and nevus of Ito on both shoulder regions since early childhood. He had bluish lesions on the right side of his hard palate. Systemic examination was normal. Relevant laboratory investigations were non contributory. The histopathological examination of the skin from the affected areas showed the presence of elongated dendritic dermal melanocytes. The present case is the first report of an association of bilateral nevus of Ito with nevus of Ota and palatal lesions. Tanino classified Nevus of Ota into four groups. As both the nevi are similar in all respect except the area of distribution, a minor modification of the existing Tanino's classification to incorporate the nevus of Ito into the classification for the Ota's nevus may be appropriate.
doi:10.4103/0019-5154.113943
PMCID: PMC3726875  PMID: 23918999
Bilateral nevus of Ito; classification; nevus of Ota; palatal lesion
14.  WT-1 expression in a spectrum of melanocytic lesions: Implication for differential diagnosis 
Journal of Cancer  2010;1:120-125.
A previous in vitro study revealed that Wilms's tumor 1 (WT-1) transcripts were detectable in 7 of 9 melanoma cell lines, but not in any of 5-normal melanocyte strains tested. Our current study assessed the expression levels of WT-1 protein in clinical samples, to determine whether the expression levels of the WT-1 protein may be used as a novel marker to assist differential diagnosis. Paraffin-embedded tissue sections from 15 cases of malignant melanomas and 25 cases of benign nevi were subjected to immunohistochemistry with a monoclonal antibody against the human WT-1 protein. The expression levels of WT-1 protein among normal, benign, and malignant melanocytes were semi-quantitatively assessed. Strong and uniform WT-1 immunoreactivities were seen in all or nearly all tumor cells in both the junctional and dermal components of all malignant melanomas, and also in a vast majority of the tumor cells of Spitz's (n = 8), recurrent (n = 2), and junction (n = 2) nevi. Distinct WT-1 immunoreactivities were also seen in some isolated individual tumor cells or tumor cell clusters in the junctional component of compound nevus (9) and in intradermal nevus (2). It is interesting to note that some isolated normal appearing melanocytes or cell clusters, and all morphologically distinct endothelial cells were strongly positive to WT-1. However, all tumor cells within the dermal component of compound (n = 9) or deep penetrating nevi (n = 1), or capsular nevus inclusion of lymph node (1) were devoid of WT-1 expression. Our findings suggest that the expression level of the WT-1 protein has no significant value in distinguishing between Spitz's nevi and malignant melanoma, but it may be a useful marker in differentiating between benign and malignant melanocytes within the dermal component. Our findings also suggest that aberrant WT-1 expression may have oncogenic properties that promote the initiation and progression of melanocytic lesions.
PMCID: PMC2938075  PMID: 20842234
Wilms' tumor 1 gene; Melanoma; Benign melanocytic lesions; Differential diagnosis
15.  Epidermolysis Bullosa Nevi: Report of a Case and Review of the Literature 
Case Reports in Dermatology  2011;3(3):235-239.
A 10-year-old female patient, being treated for dystrophic bullous epidermolysis in a Pediatric Hospital, was referred to our Dermoscopy Ambulatory because of a newly observed mole in the submandibular area. Clinically, the lesion presented as an irregular double-colored macule of about 2 cm in diameter, with irregular borders, suspicious of malignancy. Dermoscopy showed a multicomponent pattern, with multiple colors, ill-defined network, black blotches, streaks, multiple dots, a blue-whitish veil and granularity at the periphery. Although it had a clinical appearance of malignancy, dermoscopy every semester was proposed due to the revision of a recently described entity, named bullous epidermolysis nevi, that we made in these children. The fragile skin of this particular patient was also taken into account, and overtreatment was avoided. Bullous epidermolysis nevi is the term given to large, asymmetrical and often irregularly pigmented melanocytic nevi that occur in former areas of blistering in patients with the dystrophic forms of the disease. Despite its atypical clinical appearance, and sometimes also atypical dermoscopy, malignant transformation has not been reported yet. Similarly to recurrent nevi, where melanocytes proliferate in a previous area of trauma, clinical aspect, dermoscopy, and histopathology may tempt clinicians to diagnose benign moles as melanoma. Here we report one case of this entity, scarcely reported on in literature, and review clinical and dermatoscopical features of epidermolysis bullosa nevi confronting it with recurrent nevi. The usefulness of dermoscopy as a treatment strategy is stressed.
doi:10.1159/000334832
PMCID: PMC3250666  PMID: 22220143
Epidermolysis bullosa; Nevi; Dermoscopy
16.  Correlation between dermoscopic and histopathological diagnoses of atypical nevi in a dermatology outpatient clinic of the Medical School of São José do Rio Preto, SP, Brazil* 
Anais Brasileiros de Dermatologia  2013;88(2):199-203.
BACKGROUND
The incidence of cutaneous melanoma is increasing worldwide. Since it is an aggressive neoplasm, it is difficult to treat in advanced stages; early diagnosis is important to heal the patient. Melanocytic nevi are benign pigmented skin lesions while atypical nevi are associated with the risk of developing melanoma because they have a different histological pattern than common nevi. Thus, the clinical diagnosis of pigmented lesions is of great importance to differentiate benign, atypical and malignant lesions. Dermoscopy appeared as an auxiliary test in vivo, playing an important role in the diagnosis of pigmented lesions, because it allows the visualization of structures located below the stratum corneum. It shows a new morphological dimension of these lesions to the dermatologist and allows greater diagnostic accuracy. However, histopathology is considered the gold standard for the diagnosis.
OBJECTIVES
To establish the sensitivity and specificity of dermoscopy in the diagnosis of pigmented lesions suspected of malignancy (atypical nevi), comparing both the dermatoscopic with the histopathological diagnosis, at the Dermatology Service of the outpatient clinic of Hospital de Base, São José do Rio Preto, SP.
METHODS
Analysis of melanocytic nevi by dermoscopy and subsequent biopsy on suspicion of atypia or if the patient so desires, for subsequent histopathological diagnosis.
RESULTS
Sensitivity: 93%. Specificity: 42%.
CONCLUSIONS
Dermoscopy is a highly sensitive method for the diagnosis of atypical melanocytic nevi. Despite the low specificity with many false positive diagnoses, the method is effective for scanning lesions with suspected features of malignancy.
doi:10.1590/S0365-05962013000200002
PMCID: PMC3750880  PMID: 23739709
Dermoscopy; Diagnosis; Nevus, pigmented
17.  A Malignant Melanoma Associated with a Blue Nevus of the Lip 
Annals of Dermatology  2010;22(1):119-124.
Blue nevi are characterized by a collection of pigment-producing melanocytes in the dermis. These lesions clinically present as well demarcated cerulean-blue or bluish black colored papules or plaques that usually measure less than 1 cm in diameter. They are typically found on the dorsal surface of the hands and feet or in the head and neck region; however, they are rarely found in the oral cavity. These lesions are usually benign and stable over time. However, malignant melanomas developing in or associated with a blue nevus (which is also called malignant blue nevus) have been only rarely reported. A malignant blue nevus might develop in a common blue or cellular blue nevus, a giant congenital nevus or in a nevus of Ota, or it may be malignant from the start. Malignant blue nevi most commonly are found on the scalp. A malignant blue nevus of the lip has not been previously reported in the medical literature. We report here on a patient with a malignant melanoma associated with a blue nevus of the lip. The malignant melanoma was presumed to have developed from a blue nevus that was present on the upper lip of a 50-year-old male.
doi:10.5021/ad.2010.22.1.119
PMCID: PMC2883390  PMID: 20548900
Blue nevus; Malignant blue nevus; Malignant melanoma; Upper lip
18.  Diagnosing Ocular Surface Squamous Neoplasia in East Africa 
Ophthalmology  2014;121(2):484-491.
Objective
To examine the reliability of clinical examination and in vivo confocal microscopy (IVCM) in distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions.
Design
Case-control study.
Participants
Sixty individuals with conjunctival lesions (OSSN and benign) and 60 age-matched controls with normal conjunctiva presenting to Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
Methods
Participants were examined and photographed, and IVCM was performed. Patients with conjunctival lesions were offered excisional biopsy with histopathology and a human immunodeficiency virus (HIV) test. The IVCM images were read masked to the clinical appearance and pathology results. Images were graded for several specific features and given an overall categorization (normal, benign, or malignant). A group of 8 ophthalmologists were shown photographs of conjunctival lesions and asked to independently classify as OSSN or benign.
Main Outcome Measures
Comparison of the histopathology diagnosis with the clinical and IVCM diagnosis.
Results
Fifty-two cases underwent excisional biopsy with histopathology; 34 were on the OSSN spectrum, 17 were benign, and 1 was lymphoma. The cases and controls had comparable demographic profiles. Human immunodeficiency syndrome infection was more common in OSSN compared with benign cases (58.8% vs. 5.6%; odds ratio, 24.3, 95% confidence interval [CI], 2.8–204; P = 0.003). Clinically, OSSN lesions more frequently exhibited feeder vessels and tended to have more leukoplakia and a gelatinous appearance. Overall, the ophthalmologists showed moderate agreement with the histology result (average kappa = 0.51; 95% CI, 0.36–0.64). The masked grading of IVCM images reliably distinguished normal conjunctiva. However, IVCM was unable to reliably distinguish between benign lesions and OSSN because of an overlap in their appearance (kappa = 0.44; 95% CI, 0.32–0.57). No single feature was significantly more frequent in OSSN compared with benign lesions. The sensitivity and specificity of IVCM for distinguishing OSSN from benign conjunctival lesions were 38.5% and 66.7%, respectively.
Conclusions
In East Africa, conjunctival pathology is relatively common and can present significant diagnostic challenges for the clinician. In this study, neither clinical examination nor IVCM was found to reliably distinguish OSSN from benign conjunctival pathology because of an overlap in the features of these groups. Therefore, IVCM cannot currently replace histopathology, and management decisions should continue to rely on careful clinical assessment supported by histopathology as indicated.
doi:10.1016/j.ophtha.2013.09.027
PMCID: PMC3901930  PMID: 24321141
19.  The important role of interdisciplinary collaboration in the management of a melanocytic skin lesion 
Dermatology Reports  2011;3(1):e10.
One of the most confounding characteristics, commonly seen in malignant, but even in benign melanocytic nevi, is represented by the regression phenomenon. The identification of regression, through dermoscopical observation, can be predictive of a tricky histopathological examination. Therefore, this feature should be an alert to a meticulous clinical, dermoscopical and histopathological correlation for correct analysis of melanocytic skin lesions. A 26-year-old man was referred to our department for a pigmented skin lesion localized on his trunk. It was clinically and dermoscopically diagnosed as atypical melanocytic nevus with central regression. After 1 year the lesion underwent considerable changes, leading to a nearly complete regression. The lesion was excised and, on the basis of clinical, dermoscopical and histopathological correlation, was interpreted as a junctional melanocytic nevus with regression. In our case the association of clinical, dermoscopical and histopathological experience, resulted an important and useful method, in order to proper interpret and correctly diagnose an atypical melanocytic skin lesion.
doi:10.4081/dr.2011.e10
PMCID: PMC4211484  PMID: 25386254
melanocytic skin lesion; dermoscopy; histopathology; regression; interdisciplinary collaboration.
20.  DEK Expression in Melanocytic Lesions 
Human pathology  2011;42(7):932-938.
The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic and Spitz nevi) were negative or exhibited weak staining for DEK with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (p<0.0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth > 1mm) and metastatic melanomas as compared to superficial melanomas (Breslow depth ≤ 1mm) (p<0.05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression.
doi:10.1016/j.humpath.2010.10.022
PMCID: PMC3162348  PMID: 21316078
DEK; benign nevi; invasive melanomas; metastatic melanomas; melanoma progression
21.  Diagnostic transvitreal fine-needle aspiration biopsy of small melanocytic choroidal tumors in nevus versus melanoma category. 
PURPOSE: To report an experience with fine-needle aspiration biopsy of selected small melanocytic choroidal tumors during the interval from April 13, 1983, through January 19, 2001. METHODS: Retrospective descriptive case series report of 34 patients with a small melanocytic choroidal tumor (maximal diameter, < or = 10 mm; thickness, > or = 1.5 mm but < or = 3 mm) evaluated diagnostically by transvitreal fine-needle aspiration biopsy prior to treatment. None of the tumors had invasive features at the time of biopsy. RESULTS: Patients ranged in age from 26 to 73 years (mean, 50.9 years). The evaluated choroidal tumors had a mean maximal basal diameter of 8.0 mm and a mean maximal thickness of 2.4 mm. Eighteen of the 34 tumors (52.9%) had been documented to enlarge prior to biopsy. Biopsy was performed in all cases using a 25-gauge hollow lumen needle and a transvitreal approach via a pars plana puncture site. The biopsy yielded a sufficient aspirate for cytodiagnosis in 22 of 34 cases (64.7%). In these cases, the tumor was classified as malignant melanoma in 16 (47.1% of total), intermediate lesion in 4 (11.8%), and benign nevus in 2 (5.9%). The 12 tumors that yielded an insufficient aspirate and the four lesions that yielded intermediate cells continued to be classified as "nevus versus melanoma" and were monitored periodically for growth or other changes. Four of the 12 tumors that yielded an insufficient aspirate for cytodiagnosis and all four lesions that yielded intermediate cells were eventually reclassified as small choroidal melanomas and treated. The remaining eight tumors that yielded an insufficient aspirate and the two tumors that yielded benign nevus cells were classified as benign nevi at the most recent follow-up evaluation. CONCLUSIONS: Fine-needle aspiration biopsy showed that a substantial proportion of small melanocytic choroidal tumors likely to be classified clinically as small choroidal melanomas in many centers were in fact benign nevi or intermediate lesions.
PMCID: PMC1358965  PMID: 12545696
22.  NRAS and BRAF Mutations in Melanoma-Associated Nevi and Uninvolved Nevi 
PLoS ONE  2013;8(7):e69639.
According to the prevailing multistep model of melanoma development, oncogenic BRAF or NRAS mutations are crucial initial events in melanoma development. It is not known whether melanocytic nevi that are found in association with a melanoma are more likely to carry BRAF or NRAS mutations than uninvolved nevi. By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the melanoma part of 46 melanomas that developed in association with a nevus. In 25 cases we also genotyped a control nevus of the same patients. Available tissue was also immunostained using the BRAFV600E-mutation specific antibody VE1. The BRAFV600E mutation was found in 63.0% of melanomas, 65.2% of associated nevi and 50.0% of control nevi. No significant differences in the distribution of BRAF or NRAS mutations could be found between melanoma and associated nevi or between melanoma associated nevi and control nevi. In concordant cases immunohistochemistry showed a higher expression (intensity of immunohistochemistry) of the mutated BRAFV600E-protein in melanomas compared to their associated nevi. In this series the presence of a BRAF- or NRAS mutation in a nevus was not associated with the risk of malignant transformation. Our findings do not support the current traditional model of stepwise tumor progression.
doi:10.1371/journal.pone.0069639
PMCID: PMC3704624  PMID: 23861977
23.  Cystic Benign Melanosis of the Conjunctiva 
Cornea  2012;31(11):1273-1277.
Purpose
To report the clinical and histologic features of cystic benign melanosis.
Methods
This case series reports on the clinical and histopathologic features of three patients with enlarging cystic, brown pigmented conjunctival lesions.
Results
Slit lamp exam showed cystic melanotic lesions of bulbar conjunctiva. Histopathologic examination of the biopsy specimens showed epithelial lined cysts in the substantia propria, goblet cells, and secondary pigmentation of basilar keratinocytes.
Conclusions
Cystic benign melanosis, a unique conjunctival lesion, should be differentiated from cystic nevus and primary acquired melanosis (PAM).
doi:10.1097/ICO.0b013e31823d1ec4
PMCID: PMC3467456  PMID: 23044615
conjunctiva; benign melanosis; cystic melanosis; epithelial inclusion cyst; racial melanosis
24.  Squamous cell papilloma of the conjunctiva due to human papillomavirus (HPV): presentation of two cases and review of literature 
Purpose
We describe two patients with squamous cell papilloma of the conjunctiva due to human papilloma virus (HPV) and review the literature.
Patients and methods
Two patients with conjunctival tumors were examined and treated in the University Eye Clinic and diagnosed in the University Pathology Department, University Hospital of Ioannina, Greece. The first patient was a 48-year-old man presenting with an extended papillomatous lesion in bulbar conjunctiva covering part of the cornea of his right eye. The second patient was a 24-year-old man presenting with a polypoidal papillomatous lesion on the caruncle of his right eye. The two lesions were removed surgically, cryotherapy was applied to the adjacent conjunctiva, and topical mitomycin-C was used. The amniotic membrane was used to restore the conjunctival defect in the first patient. The two removed lesions were sent to the Pathology Department for histopathological examination. Immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction (PCR) analysis were performed.
Results
In the first patient, histopathology showed the presence of a benign squamous papilloma with koilocytosis. DNA in situ hybridization with broad-spectrum probes showed that this patient was positive for HPV DNA. In the second patient, histopathology showed the presence of a squamous papilloma with mild dysplasia and koilocytosis. Immunohistochemical analysis was positive for HPV protein and p16 protein. DNA in situ hybridization with broad-spectrum probes showed that the patient was positive for HPV DNA. PCR analysis showed the presence of HPV 6. According to morphological and molecular findings, both patients were diagnosed with squamous cell papilloma due to HPV.
Conclusion
HPV can infect the ocular surface. According to clinical results, the ophthalmologist in cooperation with the pathologist can recommend appropriate laboratory examinations to confirm the diagnosis and successfully treat conjunctival papillomas.
doi:10.2147/OPTH.S34999
PMCID: PMC3460712  PMID: 23055678
conjunctiva; papilloma; human papillomavirus; koilocytosis; in situ hybridization; polymerase chain reaction
25.  Epidemiology of benign eyelid lesions in patients presenting to a teaching hospital 
Saudi Journal of Ophthalmology  2011;26(2):211-216.
Purpose
This study evaluates the relative frequency of benign eyelid lesions presented to a teaching hospital in Saudi population.
Patients and methods
Charts of patients with benign eyelid lesions were retrospectively reviewed from January 2003 to December 2008. Clinical details included demographic data, symptoms and signs, surgical findings, primary diagnosis, and indication for biopsy were analyzed in a histopathologically confirmed benign eyelid lesions. Eyelid lesions were arranged according to their order of frequencies.
Results
A total of 222 biopsies were evaluated from 181 patients (male 39.2% and female 60.8%). The age of the patient at the time of biopsy ranged from 2 to 87 years old. The most common benign eyelid lesion encountered in our practice was sweat gland hidrocystoma followed by chalazion, skin tag, epidermal cyst, nevus, seborrheic keratosis, xanthelasma, and molluscum contagiosum respectively. Histopathological studies confirmed the clinical diagnosis in 95.9% (213/222) of specimens and was different from the clinical diagnosis in 4.1% (9/222) of the lesions which included seborrheic keratosis (n = 3), pilomatrixoma, steatocystoma, hemangioendothelioma, juvenile xanthogranuloma, calcinosis cutis, and syringocystadenoma papilliferum. No malignant lesion was labeled as benign.
Conclusion
Epidemiology of benign eyelid lesions in Saudi population is different from Far East or Western populations. Sweat gland hidrocystoma with classical clinical features and straightforward diagnosis is the most frequent lesion in our series which could be due to characteristic dry climate.
doi:10.1016/j.sjopt.2011.05.005
PMCID: PMC3729505  PMID: 23960994
Epidemiology; Eyelid; Benign; Lesions

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